**5. The concept of unstable atherosclerotic plaque**

has been modified by Virmani and Naghavi *et al* divides the atheromatous lesions into nonatherosclerotic intimal lesions and progressive atherosclerotic plaques. [24, 25] The classifica‐ tion, although not particularly directed at the carotid atherosclerotic lesions, is however applicable when classifying carotid plaques. Progressive atherosclerotic plaques (AHA plaque types V and VI) are relevant in the setting of clinically significant carotid disease (figure-2).

Type IV Atheroma (Fibrous Plaque), dense large extra cellular lipid core deep to intima, and close to media.

**Table 1.** American Heart Association has classification of atherosclerotic lesions [23] (*Circulation* 1995;92: 1355-74)

**Figure 2.** American Heart Association Type VI (Complicated atherosclerotic lesion) obtained from a carotid endarter‐

Type I Adaptive Lesion: Intimal Smooth Muscle Cells (SMC) Type II Fatty Streak, Foamy Macrophages and underlying SMCs

> VI a Disruption of the intimal surface VI b Intra Plaque Haemorrhage

Complicated plaque:

88 Carotid Artery Disease - From Bench to Bedside and Beyond

ectomy specimen. (*Br J Surg.* 2001;88:945–950.)

Type VI

Type III Pre Atheroma, Intimal Macrophages, deeper pools of extracellular lipid

Type V Fibroatheroma, multiple layers of lipid core encased in a fibrous cap

VI c Thrombosis related to the atherosclerotic plaque

The concept that a sub-group of atherosclerotic plaques are prone to embolisation or thrombosis is not new. As early as 1926, Benson postulated that coronary thrombosis results from disruption of intima that exposes lipids to flowing blood. [26] Constantinides was the first to establish conclusively that plaque rupture was the immediate cause of coronary thrombosis. [27] In a series of subsequent studies Davies *et al* established the importance of plaque fissuring, ulceration and subsequent thrombosis in the development of acute coronary syndromes. [28-30] Further clinical and angiographic work has led to progres‐ sion of this concept and introduction of thrombolytic therapy in the treatment of coro‐ nary artery atherosclerosis. [31-34]

Atherosclerotic plaques that are prone to rupture are known to have certain cellular, molecular and structural features. Notably these include an intense inflammatory process within the plaque, angiogenesis, and intra-plaque haemorrhage with gradual thinning of the fibrous cap, subsequent loss of plaque cap integrity and ulceration. [35] Burke *et al* defined a vulnerable plaque in the coronary arteries as a lesion with a cap thickness of less than 65 µM [36]. Gertz *et al* noted that the lipid cores were much larger in areas of atherosclerotic plaque disruption than in lesions with intact surfaces. [37-38] Inflammatory activity within the plaque is associ‐ ated with plaque ulceration and has a role in pathogenesis of intimal damage. [39]

The evolution of atheroma is modulated by innate and adaptive immune responses which are recognized histologically as presence of an inflammatory infiltrate within the lesion [40]. These processes are responsible for replication and phenotypic change within the smooth muscle cell from contractile to secretory which results in formation of plaque cap and lesion growth. Intimal endothelial cell activation results in recruitment of macrophages and lymphocytes (predominantly CD4 positive T-cells) into evolving lesion. [40] Activation of Th-1 T-cells is known to initiate a potent inflammatory cascade which in turn leads to plaque instability [41]. Inflammatory cell infiltrate is a marker for plaque vulnerability. [42-47] Several factors such as oxidized lipoproteins, infectious agents or auto-antigens *(heat shock protein)* have been considered as the putative cause of the chronic inflammatory reaction in an atherosclerotic plaque. [40] This in turn results in weakening of the connective tissue framework of the plaque. [48, 49] Smooth muscles may help to counteract some of these effects by producing matrix protein, collagen and inhibitors of matrix degrading enzymes known as metalloproteinases. [50, 51] The net result of these two processes is thought to define whether or not the plaque ruptures or remains contained by the fibrous cap.
